This is an Open Access article distributed under the terms of the Creative Com-mons Attribution License http://creativecommons.org/licenses/by/2.0, which permits unrestricted use, distri
Trang 1Open Access
R E S E A R C H
Bio Med Central© 2010 Yamashita et al; licensee BioMed Central Ltd This is an Open Access article distributed under the terms of the Creative Com-mons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduc-Research
Prescreening based on the presence of CT-scan abnormalities and biomarkers (KL-6 and SP-D) may reduce severe radiation pneumonitis after
stereotactic radiotherapy
Hideomi Yamashita*, Shino Kobayashi-Shibata, Atsuro Terahara, Kae Okuma, Akihiro Haga, Reiko Wakui, Kuni Ohtomo and Keiichi Nakagawa
Abstract
Purpose: To determine the risk factors of severe radiation pneumonitis (RP) after stereotactic body radiation therapy
(SBRT) for primary or secondary lung tumors
Materials and methods: From January 2003 to March 2009, SBRT was performed on 117 patients (32 patients before
2005 and 85 patients after 2006) with lung tumors (primary = 74 patients and metastatic/recurrent = 43 patients) in our institution In the current study, the results on cases with severe RP (grades 4-5) were evaluated Serum Krebs von den Lungen-6 (KL-6) and serum Surfactant protein-D (SP-D) were used to predict the incidence of RP A shadow of
interstitial pneumonitis (IP) on the CT image before performing SBRT was also used as an indicator for RP Since 2006, patients have been prescreened for biological markers (KL-6 & SP-D) as well as checking for an IP-shadow in CT
Results: Grades 4-5 RP was observed in nine patients (7.7%) after SBRT and seven of these cases (6.0%) were grade 5 in
our institution A correlation was found between the incidence of RP and higher serum KL-6 & SP-D levels IP-shadow in patient's CT was also found to correlate well with the severe RP Severe RP was reduced from 18.8% before 2005 to 3.5%
after 2006 (p = 0.042) There was no correlation between the dose volume histogram parameters and these severe RP
patients
Conclusion: Patients presenting with an IP shadow in the CT and a high value of the serum KL-6 & SP-D before SBRT
treatment developed severe radiation pneumonitis at a high rate The reduction of RP incidence in patients treated after 2006 may have been attributed to prescreening of the patients Therefore, pre-screening before SBRT for an IP shadow in CT and serum KL-6 & SP-D is recommended in the management and treatment of patients with primary or secondary lung tumors
Introduction
Stereotactic body radiation therapy (SBRT) has been
widely used as a safe and effective treatment method for
primary or metastatic lung tumors [1] According to the
protocol of Japan Clinical Oncology Group (JCOG) 0403
study [2,3], the absolute contraindication to SBRT was
pregnancy Relative contraindications consisted of (a) a
history of irradiation to the concerned site, (b) severe
interstitial pneumonitis or pulmonary fibrosis, (c) severe diabetes or connective tissue disease, and (d) common use of steroids However, these complications preclude other treatment methods in some cases and radiation therapy becomes the only available treatment Favorable initial clinical results, and local control rates around 90% have been reported [4-10]
Although the mechanisms are not completely under-stood, it is critical to review the biologic factors involved
in radiation lung damage Current evidence suggests that many factors and various lung parenchymal cells contrib-ute to the pathogenesis of radiation lung damage [11]
* Correspondence: yamashitah-rad@h.u-tokyo.ac.jp
1 Department of Radiology, University of Tokyo Hospital, Hongo, Bunkyo-ku,
Tokyo, Japan
Full list of author information is available at the end of the article
Trang 2The progression of radiation-induced damage is the
result of an early activation of an inflammatory reaction
leading to the expression and maintenance of an elevated
cytokine cascade [12] Kong et al [13] concluded that
blood biomarkers such as transforming growth factor
(TGF)-beta1, interleukin (IL)-6, krebs von den Lungen-6
(KL-6), surfactant proteins (SP), and IL-1ra could
accu-rately predict radiation-induced lung damage Serum
KL-6 and SP-D were also evaluated as predictive biomarlers
for radiation pneumonitis (RP) in this study
For normal tissues, the use of a single dose rather than a
conventional fractionated dose can increase the risk of
complications However, few cases with severe toxicity
have been reported [14-16] In the current study, cases of
severe RP (grades 4-5) that received SBRT for lung
tumors in our institution were evaluated In our previous
report [17], the overall incidence rate of grades 2-5 RP
was 29% (7/25 cases) and three patients (12%) died from
RP from May 2004 to April 2006 at the median follow-up
time of 18 months after completing SBRT A significant
decrease of the incidence rate of severe RP was observed
for the period entering into 2006 The purpose of this
study was to determine the risk factors of severe RP after
SBRT for primary or secondary lung tumors
Methods and materials
Subjects
From January 2003 to March 2009, SBRT was performed
on 117 patients with lung tumors in our institution SBRT
was performed for primary lung cancers in 74 cases (63%)
and for metastatic or recurrent lung tumors in 43 cases
(37%) (Table 1) These consecutive 117 patients were
evaluated retrospectively There were 98 males and 19
females, and the median age was 72 years (range; 28-84
years) Thirteen patients (11%) had a shadow of
intersti-tial pneumonitis (IP) in the CT before SBRT, 23 patients
(20%) had high serum KL-6 value, and 19 patients (16%)
had high SP-D value The upper limit of serum KL-6 and
SP-D was defined as 500.0 U/mL and 110.0 ng/mL, respectively
All patients enrolled in this study satisfied the following eligibility criteria: a) solitary or double lung tumors; b) tumor diameter < 40 mm; c) no evidence of regional lymph node metastasis; d) Karnofsky performance status scale > or = 80%; and e) tumor not located adjacent to major bronchus, esophagus, spinal cord, or great vessels Patients with an active malignant lesion other than lung were excluded Therefore, no chemotherapy was com-bined with SBRT There were 32 patients (27%) who were treated before 2005 After 2006, patients with a high risk for RP who had an obvious IP shadow on CT with a
3-mm slice before SBRT together with a high value of serum KL-6 & SP-D were excluded from receiving SBRT
In the high resolution chest CT, IP shadow was defined
as a mandatory observation beneath the pleura and a honeycomb lung IP shadows were graded by their radio-graphically estimated total lung volume as follows: slight, less than 10%; moderate, 10-50%; and severe, >50%
Planning procedure and treatment
The treatment methods which included the definition of the internal target volume (ITV) were performed accord-ing to JCOG 0403 phase II protocol [2,3] The followaccord-ing gives a brief description of the treatment methods, which were described in detail in our previous report [17] SBRT was performed daily with a central dose of 48 Gy in four fractions over 4-8 days Each CT slice was scanned with
an acquisition time of four seconds to include the whole phase of one respiratory cycle The axial CT images were transferred to a 3-dimension RT treatment-planning machine (Pinnacle3, New Version 7.4i, Philips) Spicula formation and pleural indentation were included within the ITV The mediastinal lymph nodes were not included from the irradiation field The setup margin (SM) between ITV and the planning target volume (PTV) was
5 mm in all directions There was an additional 5 mm leaf margin to PTV, according to JCOG0403 protocol, in order to make the dose distribution within the PTV more homogeneous No pairs of parallel opposing fields were used The target reference point dose was defined at the isocenter of the beam The iso-dose distribution of an SBRT treatment was shown in Figures 123
The dose limitation for pulmonary parenchyma was mean lung dose (MLD) < 18.0 Gy, percentage of total lung volume receiving greater than or equal to 20 Gy (V20) < 20%, and V15 < 25% according to JCOG0403 protocol
Radiation method
SBRT was given in at least 8 ports by linear accelerator (Elekta Synergy System, Elekta Ltd, Crawley, UK) after the Synergy system was available in our institution from February 2007 At least eight beams (I-rotation angle was
0 degree only in two beams) were used CT verification of
Table 1: Characteristics of the tumor
Biopsy proved primary lung cancer 60 51
Unconfirmed histology (suspected of
primary lung cancer)
Metastatic or recurrent lung cancer 43 37
Trang 3Figure 1 An example of dose distribution of SBRT (Pt No 5).
Figure 2 An example of dose distribution of SBRT (Pt No 7).
Trang 4the target isocenter was performed before each treatment
session using a kilovoltage-based cone-beam CT (CBCT)
unit in the same room and in a treatment position The
Linac machine was Elekta Synergy with the cone-beam
CT The details of the radiation method before 2007 were
described in our previous report [17] The collapsed cone
heterogeneous correction method for lung The
breath-ing suppression was done with a body frame and an
abdominal pressure board (Figure 4)
Definition of RP grading
The toxicity data were collected retrospectively from the
patient files Basically, the RP grading system used
fol-lowed the Common Terminology Criteria for Adverse
Events (CTCAE) v3.0, and the grades were as follows:
Grade 1, asymptomatic (radiographic findings only);
Grade 2, radiographic findings plus symptomatic and not
interfering with activities of daily living (ADL); Grade 3,
radiographic findings plus symptomatic and interfering
with ADL or O2 indicated; Grade 4, radiographic findings
plus life-threatening (ventilatory support indicated), and
Grade 5, radiographic findings plus death Patients with
mild pulmonary CT changes after SBRT were categorized
as Grade 1 The radiographic findings common to the 5
grades were (a) shadow distribution just beneath pleura,
(b) honeycomb lung, (c) traction bronchitis/dilation of
small bronchus, (d) ground-glass opacity (GGO), or (e) infiltrative shadow (consolidation), which was not recog-nized in the CT before SBRT
Follow-up
CT exams with 3-mm slices were performed at 2, 4, 6, 9,
12, 15, 18, and 24 months after SBRT for asymptomatic
Figure 4 Body frame and abdominal pressure board.
Figure 3 An example of dose distribution of SBRT (Pt No 8).
Trang 5patients Additionally, on the same day as CT, serum
KL-6, SP-D, white blood cell (WBC), lactate dehydrogenase
(LDH), C-reactive protein (CRP), and tumor markers
were measured in the blood plus an oxygen saturation
was measured from a fingertip
Statistical Analysis
The relationship between G4-5 RP and pre-SBRT factors
probabil-ity of RP was calculated and drawn applying the
Kaplan-Meier algorithms with day of treatment as the starting
point Subgroups were compared using log-rank
statis-tics Values of p < 0.05 were considered statistically
signif-icant Statistical calculations were conducted using
version 5.0 StatView software (SAS Institute, Cary, NC)
Results
The median follow up time for all 117 patients was 14.7
months (range; 0.3-76.2 months) The control rate within
the radiation field was 86.3% (101/117 cases)
RP of grade 4 or higher was observed in nine patients
(7.7%) and the median time of showing symptoms was 4.0
months (range; 0.4-6.0 months) (Table 2) All of these
nine RPs were due to acute exacerbation of IP (Figures
5678910) and steroid pulse therapy combined with an
oral anti-pneumocystis carinii drug was administered to
these patients Grade 4 RP with intubation was seen in
two cases and the other seven cases were grade 5 Grade 3
RP was seen in two patients during this time period
Grade 4 or higher RP was noted in six out of 32 patients
(18.8%) before 2005 and in only three out of 85 patients
(3.5%) after 2006 (Figure 11) This difference had a
Serum KL-6 was determined in 8 of the 9 patients with grades 4-5 RP and in 95 of the 108 patients with grades
0-3 RP Of the 8 patients with grades 4-5 RP, serum KL-6 (U/mL) was elevated in 6 patients (75%) (Table 2) Serum SP-D was determined in 7 patients with grades 4-5 RP and in 93 patients with grades 0-3 RP Of the 7 patients with grades 4-5 RP, serum SP-D (ng/mL) was evaluated in
5 patients (71%) (Table 2) Additionally, the IP shadow was seen in seven cases (78%) in the CT before SBRT within or outside of radiation field The radiation dose prescribed was within the protocol in all 117 patients The appearance of grades 4-5 RP and serum KL-6 value (1-year cumulative incidence; 32% vs 3% and log-rank p
< 0.0001 & X2 p = 0.0002), SP-D value (1-year; 29% vs 3% and log-rank p = 0.0001 & X2 p = 0.0002), or IP shadow in
CT before SBRT (1-year; 57% vs 2% and log-rank p <
Figure 5 CT images before SBRT (Pt No 5).
Table 2: Characteristics of nine patients with G4-5 of RP
Case
No.
s KL-6 S SP-D IP shadow RP
grading
Onset time
State V20
(%)
V40 (%)
MLD (cGy)
Stage PTV
(cc)
D95 (Gy)
Location
1 950 286 moderate 5 3.0 Mo Postop
erative
erative
erative
(0-500) (0-110)
Abbreviation ; NA = not available
Trang 60.0001 & X2 p < 0.0001) showed positive correlations
(Table 3)
The risk factors of RP other than serum KL-6, SP-D,
and IP shadow in CT are shown in Table 4 The mean
PTV for nine patients with severe RP was 29.4 cc (range:
7.7-120.9 cc) and was 42.5 cc (range: 7.5-239.4 cc) of for
the other low-grade RP patients None of these risk
fac-tors were different for those patients with and without
grades 4-5 RP
Discussion
This was a retrospective study to evaluate the incidence
rate and risk factors of severe RP after SBRT for primary
(74 patients), metastatic and recurrent (43 patients) lung
tumors Grades 4-5 RP were noted in 9 patients (7.7%); IP shadow in the CT, and high serum KL-6 & SP-D values before SBRT showed positive correlations with grades 4-5
RP Seven of the 117cases (6.0%) were of grade 5 in our institution After 2006, severe grades 4-5 RP were signifi-cantly reduced
According to Borst et al [15], the crude incidence rate
of grade 2 RP was 10.9% for the SBRT on 128 patients with malignant pulmonary lesions who were treated with 6-12 Gy per fraction with a median MLD of 6.4 Gy
(range: 1.5-26.5 Gy) According to Rusthoven et al [16],
grades 2-3 RP was rare, occurring in only one out of 38 patients (2.6%) with one to three lung metastases after SBRT of 48-60 Gy in 3 fractions They used the dose
con-Figure 6 CT images of radiation pneumonitis after SBRT (Pt No
5) The finding was acute exacerbation of IP.
Figure 8 CT images of radiation pneumonitis (acute exacerbation
of IP) after SBRT (Pt No 7).
Figure 7 CT images before SBRT (Pt No 7). Figure 9 CT images before SBRT (Pt No 8).
Trang 7straint of V15 < 35% According to Nagata et al [1], no
severe symptomatic pulmonary complications (NCICTC
Grade 3 or larger) were encountered Timmerman et al.
[14] reported in 2006 that a SBRT treatment dose of
60-66 Gy total in three fractions was administered during 1
to 2 weeks for 70 patients with clinically staged
T1-2N0M0 (tumor size < or = 7 cm) biopsy-confirmed
non-small cell lung cancer (NSCLC) This resulted in toxicity
of grades 3 to 5 in a total of 14 patients (20%) and grade 5
was seen in four patients (5.7%) Le QT et al [18]
reported in 2006 that after single-fraction SBRT (15-30
Gy) was performed for 32 patients (21 NSCLC and 11
metastatic tumors), two patients (6%) suffered from RP of
grade 5
Moreover, according to Rusthoven et al [16], patients
were required to have adequate lung function, which was defined as stable arterial hemoglobin saturation above 90% with minimal exertion, forced expiratory volume (FEV) of 1.0% higher than the predicted value of 40% or more than 1 L and carbon monoxide diffusing capacity (DLCO) higher than the predicted 40% value In our insti-tution, the exclusion criteria of SBRT consisted of an FEV
of 1.0% at less than 750 mL, and an obvious IP shadow on the roentgen examination according to JCOG 0403 pro-tocol
RP of grades 4-5 occurred in six out of 32 patients (18.8%) before 2005 and in only three out of 85 patients (3.5%) after 2006 (Figure 11) The significant reduction of severe grades 4-5 RP after 2006 in our institution is believed to be due to the selection of appropriate patients After 2006, patients were excluded from SBRT if they had an obvious IP shadow on the CT-scan (slice thickness 3.0 mm), and if serum KL-6 and SP-D levels were high All of the severe RP cases in our institution consisted of acute exacerbation of IP outspreading over the radiation field Admittedly, these nine patients with severe RP represent a small sample Whether our results are a coincidence that biomarkers and CT shadows are indeed significantly different in patients with grades 4-5 toxicity compared to patients without RP awaits confir-mation in further studies
KL-6 is the indicator that specificity is high for IP and is clinically evaluated for the purpose of diagnosing IP In addition, KL-6 is important as an index of the activity of
IP because it becomes significantly high for IP with
activ-Figure 10 CT images of radiation pneumonitis (acute
exacerba-tion of IP) after SBRT (Pt No 8).
Table 3: Relationship between G4-5 RP and pre-SBRT factors
Pre-SBRT
factors
cumulative incidence of G4-5 RP
log-rank
Serum KL-6
within normal
level
Serum SP-D
within normal
level
IP shadow in
CT
Trang 8ity In the human body, KL-6 does not develop in a type I
alveolus epithelial cell However, KL-6 develops in a type
II alveolus epithelial cell, in a bronchial epithelial cell, and
in a bronchus gland cell The expression of KL-6
increases in the hyperplasia of the type II of alveolus
epi-thelial cell in IP A small quantity of KL-6 is present in the liquid coating the alveolus in normal lungs, and its den-sity increases during hyperplasia of the type II alveolus epithelial cell for IP In addition, because inflammation occurs, blood vessel permeability rises, and KL-6 in the
Table 4: Risk factors of severe RP
Patients with G4-5 RP Patients without G4-5 RP p value
Patient specific factors
Pulmonary function
VC (L)
FEV 1.0 (L)
K-PS (%)
Age (y)
COPD
Treatment specific factors
Size of the PTV (cc)
Mean lung dose (Gy)
Lung V20 (%)
Target location
Abbreviation:
COPD = chronic obstructive pulmonary diseases
RP = radiation pneumonitis
G4-5 = grades 4-5
PTV = planning target vlume
FEV = Forced expiratory volume
K-PS = Karnofsky Performance status
N.S = not significant
Trang 9alveolus coating liquid shifts easily into the blood As a
result, KL-6 in the blood rises in the IP When an injury to
the lung stroma is evaluated, KL-6, SP-A, SP-D, and
MCP-1 are examined Of these, there is a report that
KL-6 was highest in both sensitivity (93.9%) and specificity
(96.3%) [19] Furthermore, SP-D levels at 50 to 60 Gy
(midway during radiation therapy) showed greater
sensi-tivity and positive predictive values for RP detection (74%
and 68%, respectively) than SP-A (26% and 21%,
respec-tively) [20]
Conclusion
The frequency of severe RP in our institution has recently
shown a decrease, by prescreening patients for serum
KL-6 and SP-D as biomarkers of severe RP When SBRT
was performed on patients presenting with an IP shadow
in CT and a high value of serum KL-6 before treatment,
severe radiation pneumonitis occurred at a high rate
Therefore, pre-screening of patients before SBRT appears
to be a useful strategy in treating lung tumors
Authors' contributions
HY collected and analyzed data and performed statistical analysis HY and SK-S
drafted the manuscript AT, KO, AH, and RW reviewed the data and revised the
manuscript KO and KN designed the study and revised the final version All
authors have read and approved the final version of the manuscript.
Competing interests
The authors declare that they have no competing interests.
Acknowledgements
None.
Author Details
Department of Radiology, University of Tokyo Hospital, Hongo, Bunkyo-ku,
Tokyo, Japan
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doi: 10.1186/1748-717X-5-32
Cite this article as: Yamashita et al., Prescreening based on the presence of
CT-scan abnormalities and biomarkers (KL-6 and SP-D) may reduce severe
radiation pneumonitis after stereotactic radiotherapy Radiation Oncology
Received: 11 February 2010 Accepted: 9 May 2010
Published: 9 May 2010
This article is available from: http://www.ro-journal.com/content/5/1/32
© 2010 Yamashita et al; licensee BioMed Central Ltd
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Radiation Oncology 2010, 5:32
Figure 11 Cumulative probability curves of severe radiation
pneumonitis of grades 4-5 divided by pre-2005 (old group) and
post-2006 (new group).
Old (N=32) 1y: 19.1r r7.0%
New (N=85) 1y: 3.6r2.1%
Kaplan-Meier method
0
20
40
60
80
100
Months
Log-rank p = 0.042
HR: 0.19 (95%CI: 0.047-0.76)